Question

Which women should take aspirin for the primary prevention of cardiovascular disease? What factors should be considered in decision making about aspirin?

Commentary from JoAnn E. Manson, MD, DrPH

Only recently have clinicians had rigorous evidence to guide decision making about the use of aspirin in the primary prevention of cardiovascular disease (CVD) in women. Although it is well established that aspirin is effective in the secondary prevention of CVD and in the treatment of acute myocardial infarction (MI) among both women and men,^[1] there had been sparse data about the benefits and risks of aspirin in primary prevention among women until results from a large-scale trial, the Women's Health Study (WHS), were reported in 2005.^[2] Previously, guidelines had been largely extrapolated from results of clinical trials in men, which had suggested that aspirin reduces the incidence of first MI by 30% to 35% while having little effect on stroke.^[3,4]

Primary Prevention Results in Women, Including Results Stratified by Age

The WHS, the only large primary prevention trial of aspirin in women, suggested a different pattern of cardiovascular outcomes with aspirin in women compared to men. The WHS evaluated the benefits and risks of low-dose aspirin (100 mg on alternate days) in the primary prevention of major cardiovascular events (MI, stroke, and cardiovascular death) among 39,876 initially healthy women age 45 and over, followed for 10 years.^[2] Overall, the trial showed a statistically nonsignificant 9% reduction in the primary outcome of major cardiovascular events. In contrast to the significant reduction in MI and neutral effect on stroke observed in the Physicians' Health Study^[3] and other primary prevention trials in men,^[4] the WHS demonstrated that aspirin significantly lowered the risk of total stroke by 17% (95% confidence interval, 1% to 31%) and the risk of ischemic stroke by 24% (7% to 37%) in women, but did not lower the risk of MI or cardiovascular death. As expected, aspirin increased bleeding risks. Gastrointestinal hemorrhages requiring transfusion were 40% more common with aspirin, and there was also a nonsignificant 24% increase in hemorrhagic stroke risk.

However, age appeared to be a key determinant of a woman's cardiovascular response to aspirin and her benefit/risk ratio with treatment.^[2] Among WHS participants over age 65, aspirin was associated with clear evidence of benefit: a statistically significant 26% (8%-41%) reduction in risk of major cardiovascular events, with a significant benefit on both ischemic stroke (relative risk [RR], 0.70) and MI (RR, 0.66). In contrast, for younger participants, aspirin appeared to provide little or no cardiovascular protection (RR of major CVD events, 1.01 in women ages 45-54; 0.98 in women ages 55-64) and MI risk was not reduced in either group (RR, 1.23 and 1.17, respectively). Testing for statistical interaction by age group revealed P values for interaction of 0.05 for major CVD events and 0.03 for MI. In a benefit/risk assessment by age group, the 4,097 women who were over age 65 at enrollment experienced 44 fewer major CVD events with aspirin than with placebo (P = 0.008) but had 16 more gastrointestinal hemorrhages requiring transfusion (P = 0.05). In contrast, women under age 65 had no reduction in major CVD events, while experiencing a similar increase in gastrointestinal bleeding (leading to a net adverse effect and an unfavorable benefit/risk ratio). A woman's age appeared to be a stronger predictor of her benefit/risk ratio with aspirin than her Framingham risk score, but few women in the cohort had high 10-year coronary risks.

Meta-analyses of Aspirin in Primary and Secondary Prevention of CVD

Meta-analyses confirm that, in the high-risk setting of prevalent CVD or acute MI, both men and women benefit comparably from the use of aspirin.^[1] Thus, in the absence of contraindications, aspirin should be used consistently in men and women for the secondary prevention of CVD. However, meta-analyses of aspirin in primary prevention, heavily weighted by the results of the large-scale Physicians' Health Study and WHS, suggest sex-based differences in effects: aspirin significantly reduces the risk of MI but not stroke in men and significantly reduces the risk of stroke but not MI in women.^[2] Age is an important modulator of the effect of aspirin in women. Among women younger than age 65, aspirin does not reduce major CVD events, while women age 65 and older experience reductions in MI, stroke, and composite CVD events with aspirin therapy. Randomized trial data are not available to assess the efficacy or safety of long-term aspirin use for the prevention of other diseases, such as colorectal cancer.

Conclusion

Recent randomized trials have informed decision making about the use of aspirin in the prevention of CVD in women. Aspirin should be used consistently in the secondary prevention setting in both men and women for prevention of recurrent events, in the absence of contraindications (eg, a history of serious gastrointestinal bleeding or aspirin allergy). In the primary prevention setting, the WHS findings indicate that women age 65 and older are likely to experience a net benefit from preventive low-dose aspirin therapy and should be considered for such therapy unless contraindicated. Most experts would recommend a dose of 81 mg to 100 mg daily, although higher doses may be required for patients with diabetes or established CVD. For most women below age 65, the WHS suggests that the risks of aspirin may outweigh the benefits. It is not known, however, whether subgroups of younger women at elevated CVD risk may benefit from aspirin or whether higher doses are needed for heart protection. The available evidence does not support the routine use of aspirin in women younger than age 65 for coronary protection unless they are at elevated risk by virtue of a high coronary risk score (high 10-year risk by the Framingham or Reynold's Risk Score) or the presence of diabetes, a position also taken by the American Heart Association.^[5]

From the NAMS Menopause e-Consult-newsletter released January 2009

For more, please visit http://www.menopause.org/Members/eConsulteNewsletter.aspx